rs201143364

Variant names:

• chr15-73323628-G-A
• rs201143364
• NM_005477.3:c.2465C>T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005477.3(HCN4):​c.2465C>T​(p.Thr822Met) variant causes a missense change. The variant allele was found at a frequency of 0.000211 in 1,599,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T822T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: HCN4 NM_005477.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.15

Genes affected

HCN4 (HGNC:16882): (hyperpolarization activated cyclic nucleotide gated potassium channel 4) This gene encodes a member of the hyperpolarization-activated cyclic nucleotide-gated potassium channels. The encoded protein shows slow kinetics of activation and inactivation, and is necessary for the cardiac pacemaking process. This channel may also mediate responses to sour stimuli. Mutations in this gene have been linked to sick sinus syndrome 2, also known as atrial fibrillation with bradyarrhythmia or familial sinus bradycardia. Two pseudogenes have been identified on chromosome 15. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056788623).
• BP6: Variant 15-73323628-G-A is Benign according to our data. Variant chr15-73323628-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 389291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3	c.2465C>T	p.Thr822Met	missense_variant	Exon 8 of 8	ENST00000261917.4	NP_005468.1
HCN4	XM_011521148.3	c.1247C>T	p.Thr416Met	missense_variant	Exon 7 of 7		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.2465C>T	p.Thr822Met	missense_variant	Exon 8 of 8	1	NM_005477.3	ENSP00000261917.3

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000564

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000277 AC: 65 AN: 234478 Hom.: 0 AF XY: 0.000251 AC XY: 32 AN XY: 127620

Gnomad AFR exome AF: 0.0000637

Gnomad AMR exome AF: 0.0000876

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000336

Gnomad FIN exome AF: 0.00127

Gnomad NFE exome AF: 0.000374

Gnomad OTH exome AF: 0.000341

GnomAD4 exome AF: 0.000209 AC: 303 AN: 1447608 Hom.: 0 Cov.: 35 AF XY: 0.000210 AC XY: 151 AN XY: 719832

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000674

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000701

Gnomad4 FIN exome AF: 0.00146

Gnomad4 NFE exome AF: 0.000194

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000564

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.000421 AC: 51

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Jun 24, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25642760, 24607718) -

Brugada syndrome 8 Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Nov 02, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.057	T
MetaSVM	Uncertain	0.054	D
MutationAssessor	Benign	1.5	L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.089	T
Polyphen		1.0	D
Vest4		0.090
MVP		0.85
MPC		0.18
ClinPred		0.053	T
GERP RS		3.5
Varity_R		0.058
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201143364; hg19: chr15-73615969; COSMIC: COSV99983876;